Resistance to immune checkpoint inhibitors and the tumor microenvironment

Immune checkpoint inhibitors (ICIs) have contributed significantly to the treatment of various types of cancer, including skin cancer. However, not all patients respond; some patients do not respond at all (primary resistance), while others experience recurrence after the initial response (acquired resistance). Therefore, overcoming ICI resistance is an urgent priority. Numerous ICI resistance mechanisms have been reported. They are seemingly quite complex, varying from patient to patient. However, most involve T cell activation processes, especially in the tumor microenvironment (TME). ICIs exert their effects in the TME by reactivating suppressed T cells through inhibition of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Thus, this review focuses on the resistance mechanisms based on the T cell activation process. Here, we classify the main mechanisms of ICI resistance into three categories based on: (1) antigen recognition, (2) T cell migration and infiltration, and (3) effector functions of T cells. By identifying and understanding these resistance mechanisms individually, including unknown mechanisms, we seek to contribute to the development of novel treatments to overcome ICI resistance.

This is the peer reviewed version of the following article: [Kawashima, S, Togashi, Y. Resistance to immune checkpoint inhibitors and the tumor microenvironment. Exp Dermatol. 2022; 00: 1- 10. doi:10.1111/exd.14716], which has been published in final form at [https://doi.org/10.1111/exd.14716]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages there of by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

This full-text will be available in Nov. 2023.